The objective of this research is to develop a fiber optic-based implementation of Angle-resolved Low Coherence Interferometry (a/LCI), a novel optical technique based on interferometric detection of elastically scattered light, for the purpose of probing the cellular morphology of human esophageal epithelium. The ability of a/LCI to obtain quantitative measurements of cellular characteristics such as nuclear size and chromatin texture, without the need for neither exogenous stains nor fixatives, makes it an excellent candidate to become a screening tool for in vivo detection of pre-cancerous tissue states such as intraepithelial neoplasia. As its name implies, a/LCI detects the angular distribution of scattered light using a low-coherence interferometer. The technique enables selective detection of the optical field scattered from a small region within probed tissue by exploiting the coherence properties of broadband light. The ability to probe sub-surface cellular morphology is especially important for detecting pre-cancerous changes in epithelial tissues, where changes in the basal cell layer, approximately 100 mu/m beneath the surface, are most diagnostic of tissue health. The long-range goal of this research is to create a new a/LCI-based biomedical diagnostic technique for the purpose of endoscopically identifying and monitoring neoplastic transformation in human epithelial tissues. The research plan proposed here will evaluate the feasibility of creating clinical instrumentation based on a/LCI by achieving the following milestones during the initial R21 (year 1) phase: (1) development of a rapid scanning a/LCI prototype which establishes the feasibility of measuring angular distributions via optical fiber; (2) demonstration of the capabilities of the new prototype system using tissue phantoms and in vitro cell cultures; and (3) characterization of the sensitivity of the new prototype system in probing nuclear morphology in ex vivo human tissues. During the subsequent R33 phase of the research plan, we will refine a/LCI as a clinical technique by achieving the following milestones: (1) implement a portable rapid scanning a/LCI system which uses an optical fiber probe and apply it to freshly excised human tissues, (2) develop an endoscope-compatible version of the portable a/LCI system and validate its functionality with in vivo nuclear morphology measurements of human esophageal tissues and (3) refine the endoscopic a/LCI system to enable forward and sideways views and demonstrate its utility with in vivo clinical application.